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Good fences make good neighbors

Munich, 01/25/2013

Nature abhors a vacuum, they say, but it also prefers sharp boundaries. LMU researchers have now come up with a theoretical model of how nature establishes such stable demarcations.

Embryonic development for example is a succession of such all-or-none states. Thus, the fertilized egg first gives rise to a homogeneous mass of cells, which goes on to become a collection of differentiated cell and tissue types. The boundaries between different cell types are sharply defined and are normally stable to perturbation. A research group led by LMU biophysicist Professor Erwin Frey, a member of the Nanosystems Initiative Munich (NIM), has now asked why such interfaces are so sharply defined and at the same time virtually impervious to distortion.

Drawing the line
The starting signal for cell differentiation during embryogenesis of the fruitfly comes from the mother, and forms a concentration gradient by diffusing from a localized source at one end of the egg. The nuclei formed by division after fertilization are thus exposed to different concentrations of the signal depending on their distance from one pole of the egg. However, such a smooth gradient cannot encode a simple yes-no differentiation of cell states. To do this, the maternal signal gradient must be modulated by at least two non-linear processes.

The maternal signal controls the synthesis of a specific protein, which causes cells to differentiate into head structures, while the trunk region of the embryo forms where the protein is absent. A defined ON/OFF boundary is established where the rate of change of the protein concentration within the cell mass is highest. One mechanism that contributes to this precise demarcation is known: where the concentration of the protein exceeds a certain threshold, it actively promotes its own synthesis. But according to the model developed by the Munich researchers, this modulation by self-activation is not sufficient to allow a sharp border to emerge. “In our generalized model, we show that a second non-linear mechanism is required,” says Steffen Rulands, the first author of the study.

Coping with perturbations
The team also looked at how the system responds to various perturbations, so as to ensure that the position of such boundaries remain more or less fixed.

Extrinsic factors, such as changes in ambient temperature, can lead to shifts in the relative position of the boundaries between two cell types. In addition, random internal fluctuations, conventionally referred to as noise, must be taken into account.

A cell is a small unit which contains only a relatively limited number of protein molecules. Therefore, small stochastic variations can affect the response of the whole system.

The calculations carried out by the Munich researchers indicate that the organism must choose whether to minimize intrinsic or extrinsic perturbations. It must then put up with the effects of the “uncontrolled” source, or devote minimal amounts of energy to reducing its effects. Thus, to dampen the effects of noise, the organism could increase the total number of proteins in the system, whereas the influence of temperature variations can be held in check by developing an isolation layer.

These new insights into the principles underlying the definition of stable boundaries in natural systems could also be of use to specialists in other disciplines. For example, they are applicable to the control of biochemical reactions in biotechnology, and in understanding the processes that prepare cells for division, or the factors that limit species dispersal. (Phys. Rev. Lett.) NIM

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